The second Notch Signaling in Development, Regeneration & Disease meeting, to be held July 19-25, 2014 at Bates College, Maine, will address an unmet need in the scientific community, both academic and industrial. The broad and long-term goal of this conference is to enhance cross-disciplinary discussions and collaborations in this rapidly expanding field and to better address the myriad of mechanistic, developmental, organismal, clinical and therapeutic challenges met by practitioners in the field. The Notch signaling pathway is a central mediator of short-range inter-cellular communication in metazoans, under study since 1917 in Drosophila, in other model organisms since the 1980's, and in human health since 1991. More recent studies have established that alterations in Notch activity underlie several developmental syndromes (Alagille's Syndrome, Spondylocostal Dysostosis, aortic valve disease), adult onset diseases (CADASIL, various heart and valve malformations, muscular dystrophy, multiple sclerosis) and cause or contribute to cancer initiation, promotion or progression in a tissue-dependent manner. These pathologies reflect both loss of function (e.g., Alagille's, CADASIL) and gain of function (e.g., cancer). Because the Notch signaling pathway is unique in its reliance on proteases, in the paucity of signal modulators, and because it is repeatedly used in many organs throughout adult life, the road to chronic management of Notch signaling in disease is obscured by many untoward outcomes with available therapies. The main strategy currently practiced in anti-tumor campaigns is based on g-secretase inhibitors or antagonistic antibodies; however, due to their indiscriminate inhibition of Notch receptors in all organs, toxicity upon chronic administration remains a formidable challenge. Expanding the interest in this pathway beyond developmental biology and cancer prevention is the realization that a great hurdle in Alzheimer's disease research is the difficulty in developing reliable Notch-sparing g-secretase inhibitors capable of inhibiting APP cleavage. Solving these puzzles requires outside the box thinking. The Specific Aims for this interdisciplinary yet pathway-focused meeting is to bring together a diverse community of scientists working in every model organism and on nearly every organ system from academia, biotech and the pharmaceutical industry. The participants represent diverse approaches to study Notch function and regulation in normal and pathological contexts, which will further facilitate discovery and drug development efforts. The 40 projected speakers represent a blend of established world leaders with vast institutional memory and future leaders with exciting new findings to present. Significantly, the informal and confidential environment in Gordon conferences (GRCs), and the time provided for informal interactions, will create a forum in which cutting edge technologies, ideas and discoveries can be freely exchanged, stimulating new ideas. Most importantly, the combined GRC/GRS format excels in integrating students, postdocs and investigators wishing to enter a new field, such as the study of this important signaling pathway.